Progress has been made in several of the aims of the project. The proinflammatory myeloid cell receptor TREM-1 controls Kupffer cell activation and development of hepatocellular carcinoma. Chronic inflammation drives liver cancer pathogenesis, invasion, and metastasis. Liver Kupffer cells have crucial roles in mediating the inflammatory processes that promote liver cancer. In collaboration with Anatolij Horuzsko, Georgia Health Sciences University we found that the TREM1 innate receptor control Kuppfer cell activation and development of hepatocellular carcinoma in the diethylnitrosamine (DEN) model as as inflammation, liver injury and fibrinogenesis in a mouse model of chronic liver injury induced by CCl4. In collaboration with Tim Greten, CCR, we demonstrated that that altering commensal gut bacteria in mice induces a liver-selective antitumor effect, with an increase of hepatic CXCR6+ natural killer T (NKT) cells and heightened IFN-gamma production. In vivo studies showed that NKT cells mediated liver-selective tumor inhibition. NKT cell accumulation was regulated by CXCL16 expression in liver sinusoidal endothelial cells, which was controlled by gut microbiome-mediated primary-to-secondary bile acid conversion. We studied the role of inflammatory receptors and cytokines in skin and colon chemical carcinogenesis. Signaling through the adaptor protein MyD88 promotes carcinogenesis in several cancer models. In contrast, MyD88 signaling has a protective role in the development of azoxymethane (AOM)/ dextran sodium sulfate (DSS) colitis-associated cancer (CAC). The inability of Myd88-/- mice to heal ulcers generated upon injury creates an altered inflammatory environment that induces early alterations in expression of genes encoding pro-inflammatory and growth factors increasing adenoma formation and progression to infiltrating adenocarcinomas with frequent clonal mutations in the beta-catenin gene. This study revealed a previously unknown level of complexity surrounding MyD88 activities downstream of different receptors that impact tissue homeostasis and carcinogenesis. Constitutively active RAS plays a central role in the development of human cancer and is sufficient to induce tumors in two-stage skin carcinogenesis. RAS-mediated tumor formation is commonly associated with up-regulation of cytokines and chemokines that mediate an inflammatory response considered relevant to oncogenesis. Mice lacking IL-1R or MyD88 are less sensitive to topical skin carcinogenesis than their respective WT controls. MyD88(-/-) or IL-1R(-/-) keratinocytes expressing oncogenic RAS are hyperproliferative and fail to up-regulate proinflammatory genes or down-regulate differentiation markers characteristic of RAS-expressing WT keratinocytes. Using both genetic and pharmacological approaches, we find that the differentiation and proinflammatory effects of oncogenic RAS in keratinocytes require the establishment of an autocrine loop through IL-1alpha, IL-1R, and MyD88 leading to phosphorylation of IkBalpha and NF-kB activation.. Collectively, these results demonstrate that MyD88 exerts a cell-intrinsic function in RAS-mediated transformation of keratinocytes. We recently showed that skin tumor promotion also required intact MyD88/NF-kappaB signaling in keratinocytes and an IL-17+ T cell population. TPA treated MyD88 deficient keratinocytes failed to elaborate cytokines and chemokines required to attract T cells into the skin microenvironment. Conversely, IL-17+ T cells lacking MyD88 failed to infiltrate TPA-treated skin, preventing tumor formation. IL-17 stimulated proliferation and inhibited differentiation of normal keratinocytes and elicited an IKBzeta and protein kinase C dependent expression of molecules essential for tumor promotion. IL-17 elevated IKBzeta and chemokine expression in RAS transformed human and mouse keratinocytes. Deletion of IKBzeta in RAS transformed mouse keratinocytes reduced tumor formation. Expression of transcripts common to RAS transformation were reduced in gene set enrichment analysis of IKBZ deficient RAS transformed keratinocytes. These studies define IKBzeta as an essential mediator of RAS transformation and provide a roadmap through which IL-17 contributes to tumor formation. Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth. Approximately 2% of colorectal cancer is linked to pre-existing inflammation known as colitis-associated cancer, but most develops in patients without underlying inflammatory bowel disease. Colorectal cancer often follows a genetic pathway whereby loss of the adenomatous polyposis coli (APC) tumor suppressor and activation of beta-catenin are followed by mutations in K-Ras, PIK3CA and TP53, as the tumor emerges and progresses. Curiously, however, 'inflammatory signature' genes characteristic of colitis-associated cancer are also upregulated in colorectal cancer. Further, like most solid tumors, colorectal cancer exhibits immune/inflammatory infiltrates, referred to as 'tumor-elicited inflammation'. Although infiltrating CD4(+) T(H)1 cells and CD8(+) cytotoxic T cells constitute a positive prognostic sign in colorectal cancer, myeloid cells and T-helper interleukin (IL)-17-producing (T(H)17) cells promote tumorigenesis, and a 'T(H)17 expression signature' in stage I/II colorectal cancer is associated with a drastic decrease in disease-free survival. Despite its pathogenic importance, the mechanisms responsible for the appearance of tumor-elicited inflammation are poorly understood. Many epithelial cancers develop proximally to microbial communities, which are physically separated from immune cells by an epithelial barrier. We investigated mechanisms responsible for tumor-elicited inflammation in a mouse model of colorectal tumorigenesis, which, like human colorectal cancer, exhibits upregulation of IL-23 and IL-17. We showed that IL-23 signaling promotes tumor growth and progression, and development of an anti-tumor IL-17 response. IL-23 is mainly produced by tumor-associated myeloid cells that are likely to be activated by microbial products, which penetrate the tumors but not adjacent tissue. Both early and late colorectal neoplasms exhibit defective expression of several barrier proteins. We propose that barrier deterioration induced by colorectal-cancer-initiating genetic lesions results in adenoma invasion by microbial products that trigger tumor-elicited inflammation, which in turn drives tumor growth. We reported that a similar pathway regulated by the interplay between cytokine signaling and microbiota also affect atherosclerosis. IL-23 and its downstream target IL-22 restricted atherosclerosis by repressing pro-atherogenic microbiota. Inactivation of IL-23-IL-22 signaling led to deterioration of the intestinal barrier, dysbiosis, and expansion of pathogenic bacteria with distinct biosynthetic and metabolic properties, causing systemic increase in pro-atherogenic metabolites such as lipopolysaccharide (LPS) and trimethylamine N-oxide (TMAO). Augmented disease in the absence of the IL-23-IL-22 pathway was mediated in part by pro-atherogenic osteopontin, controlled by microbial metabolites. Microbiota transfer from IL-23-deficient mice accelerated atherosclerosis, whereas microbial depletion or IL-22 supplementation reduced inflammation and ameliorated disease. Our work uncovers the IL-23-IL-22 signaling as a regulator of atherosclerosis that restrains expansion of pro-atherogenic microbiota and argues for informed use of cytokine blockers to avoid cardiovascular side effects driven by microbiota and inflammation.